Three New Studies on Human Milk

Title: Macronutrient analysis of modified-fat breast milk produced by 3 methods of fat removal.

In: JPEN (Journal of Parenteral and Enteral Nutrition) 2019 Sep 17. doi: 10.1002/jpen.1710. [Epub ahead of print]

Authors: Barbas KH, O'Brien K, Forbes PW, Belfort MB, Connor JA, Thiagarajan RR, Huh S.

Abstract "Background: Infants with chylothorax after congenital heart disease surgery are commonly treated using modified-fat breast milk. The effect of fat removal on breast milk macronutrients remains unclear. We compared macronutrient content of breast milk with breast milk skimmed using 3 methods, including a novel device, a cream separator. Methods: Thawed frozen breast milk samples from 30 women were defatted using refrigerated centrifuge, cream separator, and manual separation after refrigeration. We used standard assays to measure energy, protein, and fat content of breast milk samples. Results: All fat removal methods yielded skimmed breast milk with substantially lower fat and energy content. Mean energy content in breast milk skimmed by centrifuge (36.7 [SD 3.6] kcal/100 mL) was similar to that from cream separator (38.8 [3.5] kcal/100 mL). Both centrifuge and cream separator methods removed almost all fat and substantially more fat than the manual fat removal method. For unprocessed milk, energy and fat content estimated by creamatocrit was similar to reference method measurements; in skimmed milk, the creamatocrit significantly overestimated fat content. Mean protein content of skimmed breast milk was similar to unprocessed breast milk (mean 1.25 [0.31] g/100 mL). Conclusion: Breast milk fat removal did not significantly alter protein levels. In skimmed breast milk, the overestimation of fat content using creamatocrit method suggests a need for more accurate bedside methods to assess macronutrient content. The similar macronutrient composition of breast milk skimmed by cream separator and centrifuge suggests the potential for cream separator use as a new, portable defatting method for hospitals and families."

Abstract only: https://onlinelibrary.wiley.com/doi/abs/10.1002/jpen.1710

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Title: Milk analysis using milk analyzers in a standardized setting (MAMAS) study: A multicentre quality initiative.

In: Clinical Nutrition (Edinburgh, Scotland) 2019 Sep 3. pii: S0261-5614(19)33040-7. doi: 10.1016/j.clnu.2019.08.028. [Epub ahead of print]

Authors: Kwan C, Fusch G, Rochow N, Fusch C; MAMAS Study collaborators.

Abstract "Background: Human milk analyzers are increasingly used to rapidly measure the macronutrient content in breast milk for individual target fortification, to reduce the risk of postnatal growth restriction. However, many milk analyzers are used without calibration, validation or quality assurance. Aims: To investigate measurement quality between different human milk analyzers, to test whether accuracy and precision of devices can be improved by establishing individual calibration curves, and to assess long-term stability of measurements, following good clinical laboratory practice (GCLP). Methods: Sets of identical breast milk samples were sent to 13 participating centres in North America and Europe, for a total of 15 devices. The study included 3 sets of samples: A) initial assessment of the device's performance consisting of 10 calibration samples with random replicates; B) long term stability and quality control consisting of 2 batches of samples to be measured every time before the device is used, over 6 months; C) ring trial consisting of 2 samples to be measured monthly. The devices tested were Unity SpectraStar (n = 5) and MIRIS Human Milk Analyzer (n = 10). Results: There are significant variations in accuracy and precision between different milk analyzers' fat, protein and lactose measurements. However, the accuracy of measurements can be improved by establishing individual correction algorithms. Repeated measurements are more robust when coming from a larger batch volume. Long term stability also varies between devices. Conclusion: The variations in measurements between devices are clinically significant and would impact both daily dietary prescriptions, and the outcomes of clinical studies assessing the effect of targeted adjustment of nutrient intake in preterm babies. This study shows that it is crucial to follow GCLP when using milk analyzers to ensure proper measurement of macronutrients, similar to what is required of other medical devices."

Open access: https://www.clinicalnutritionjournal.com/article/S0261-5614(19)33040-7/fulltext

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Title: The milk protein alpha-casein suppresses triple negative breast cancer stem cell activity via STAT and HIF-1alpha signalling pathways in breast cancer cells and fibroblasts.

In: Journal of Mammary Gland Biology and Neoplasia. 2019 Sep 12. doi: 10.1007/s10911-019-09435-1. [Epub ahead of print]

Authors: Garner KEL, Hull NJ, Sims AH, Lamb R, Clarke RB.

Abstract "Triple negative breast cancer (TNBC) is the most lethal breast cancer subtype. Extended periods of lactation protect against breast cancer development, but the mechanisms underlying this protection are unknown. We examined the effects of the milk protein alpha-casein over expression in the triple negative MDA-MB-231 breast cancer cell line. The effects of recombinant alpha-casein added exogenously to MDA-MB-231 breast cancer cells, and immortalised human fibroblasts were also investigated. We used transcriptional reporters to understand the signalling pathways downstream of alpha-casein in breast cancer cells and these fibroblasts that were activated by breast cancer cells. To extend our findings to the clinical setting, we analysed public gene expression datasets to further understand the relevance of these signalling pathways in triple negative breast cancer cells and patient samples. Finally, we used small molecular inhibitors to target relevant pathways and highlight these as potential candidates for the treatment of TN breast cancer. High levels of alpha-casein gene expression were predictive of good prognosis across 263 TNBC patient tumour samples. Alpha-casein over expression or exogenous addition reduces cancer stem cell (CSC) activity. HIF-1alpha was identified to be a key downstream target of alpha-casein, in both breast cancer cells and activated fibroblasts, and STAT transcription factors to be upstream of HIF-1alpha. Interestingly, HIF-1alpha is regulated by STAT3 in breast cancer cells, but STAT1 is the regulator of HIF-1alpha in activated fibroblasts. In analysis of 573 TNBC patient samples, alpha-casein expression, inversely correlated to HIF-1alpha, STAT3 and STAT1. STAT1 and STAT3 inhibitors target HIF-1alpha signalling in activated fibroblasts and MDA-MB-231 breast cancer cells respectively, and also abrogate CSC activities. Our findings provide an explanation for the protective effects of lactation in TNBC. Clinical data correlates high alpha-casein expression with increased recurrence-free survival in TNBC patients. Mechanistically, alpha-casein reduces breast cancer stem cell activity in vitro, and STAT3 and STAT1 were identified as regulators of pro-tumorigenic HIF-1alpha signalling in breast cancer cells and fibroblasts respectively."

Open access: https://link.springer.com/article/10.1007%2Fs10911-019-09435-1

New Studies on Human Milk

Some new studies and a review article:

Title: Evaluation of macronutrient content of fresh and frozen human milk over 6 months.

In: The Journal of Maternal-Fetal & Neonatal Medicine 2019 Aug 8:1-8. doi: 10.1080/14767058.2019.1651269. [Epub ahead of print].

Authors: Tanriverdi S, Koroglu O, Uygur Ö, Yalaz M, Kultursay N.

Abstract: "Aim: In this study, we aimed to see the time-dependent changes in the macronutrient content of early frozen breast milk and also to compare it with fresh breast milk in the first 6 months. Materials and method: We evaluated the milk samples of 43 mothers who delivered at term. Milk samples after the first 15 days following delivery were expressed and collected dividing into seven aliquots to be stored frozen at -20 °C. Every month freshly collected new milk samples were analyzed together with one aliquot of the stored samples, up to 6 months. The energy, protein, lipid, and carbohydrate contents of samples were analyzed by Miris Human Milk Analyzer. Results: In the first 3 months, fresh milk had higher caloric and lipid content when compared to frozen samples. The protein content of fresh milk decreased after 2 months and became lower than frozen samples. The energy and lipid content of frozen milk decreased over time but protein and carbohydrate contents stayed stable. Carbohydrate content of fresh and frozen samples did not show major changes. Conclusion: It may be more suitable to consume the frozen milk that was collected in the early weeks of delivery within first 2 months."

Abstract only: https://www.tandfonline.com/doi/abs/10.1080/14767058.2019.1651269?journalCode=ijmf20

Title: Determinants of persistent organic pollutant (POP) concentrations in human breast milk of a cross-sectional sample of primiparous mothers in Belgium.

In: Environment International 2019 Aug 3;131:104979. doi: 10.1016/j.envint.2019.104979. [Epub ahead of print]

Authors: Aerts R, Van Overmeire I, Colles A, Andjelković M, Malarvannan G, Poma G, Den Hond E, Van de Mieroop E, Dewolf MC, Charlet F, Van Nieuwenhuyse A, Van Loco J, Covaci A.

Abstract: "BACKGROUND: Bio-accumulation of persistent organic pollutants (POPs) in the environment and in the food chain can lead to high pollutant concentrations in human fat-containing tissues and breast milk. OBJECTIVES: We aimed to identify the maternal characteristics that determined POP concentrations in breast milk of primiparous mothers in Belgium. METHODS: Breast milk samples were obtained from a cross-sectional sample of 206 primiparous mothers in 2014. POP concentrations in breast milk samples were determined by GC-ECNI-MS and GC-EI-MS/MS depending on the analytes' sensitivity. Associations between POP concentrations in breast milk and potential determinants were investigated using two-way contingency tables and multivariable generalized linear models. RESULTS: Fifteen of the 23 screened POPs were detected in the breast milk samples. Four organochlorine compounds (p,p'-DDT, p,p'-DDE, HCB and β-HCH) and two brominated flame retardant congeners (BDE-47, BDE-153) were detected at concentrations above the limit of quantification in >50% of the breast milk samples. Maternal age and BMI were usually associated with higher POP concentrations. Rural residency and consumption of home-produced eggs, fatty fish and fish oil supplements were associated with higher concentrations of DDT and DDE. Consumption of fatty fish and being breastfed during childhood were associated with higher concentrations of HCB and β-HCH. Fish oil supplements and home-produced eggs were associated with higher concentrations of BDEs, but for BDE congeners exposure routes other than diet require further investigation. CONCLUSIONS: Dietary and non-dietary determinants predict individual POP concentrations in breast milk."

Open access: https://www.sciencedirect.com/science/article/pii/S0160412019309080?via%3Dihub

Title: In Vitro Digestion of Human Milk: Influence of the Lactation Stage on the Micellar Carotenoids Content.

In: Antioxidants 2019, 8(8), 291; https://doi.org/10.3390/antiox8080291.

Authors: Ana A. O. Xavier, Juan E. Garrido-López, Josefa Aguayo-Maldonado, Juan Garrido-Fernández, Javier Fontecha, Antonio Pérez-Gálvez.

Abstract: "Human milk is a complex fluid with nutritive and non-nutritive functions specifically structured to cover the needs of the newborn. The present study started with the study of carotenoid composition during progress of lactation (colostrum, collected at 3-5 d postpartum; mature milk, collected at 30 d postpartum) with samples donated from full-term lactating mothers (women with no chronic diseases, nonsmokers on a regular diet without supplements, n = 30). Subsequently, we applied an in vitro protocol to determine the micellarization efficiency of the carotenoids, which were separated by HPLC and quantified by the external standard method. That in vitro protocol is tailored for the biochemistry of the digestive tract of a newborn. To the best of our knowledge, the present study is the first report of carotenoids micellar contents, obtained in vitro. This study reveals, from the in vitro perspective, that colostrum and mature milk produce significant micellar contents of carotenoids despite lipids in milk are within highly complex structures. Indeed, the lactation period develops some influence on the micellarization efficiency, influence that might be attributed to the dynamics of the milk fat globule membrane (MFGM) during the progress of lactation."

Open access: https://www.mdpi.com/2076-3921/8/8/291

Title: The Functional Power of the Human Milk Proteome. [Review article]

In: Nutrients 2019 Aug 8;11(8). pii: E1834. doi: 10.3390/nu11081834.

Authors: Zhu J, Dingess KA.

Abstract: "Human milk is the most complete and ideal form of nutrition for the developing infant. The composition of human milk consistently changes throughout lactation to meet the changing functional needs of the infant. The human milk proteome is an essential milk component consisting of proteins, including enzymes/proteases, glycoproteins, and endogenous peptides. These compounds may contribute to the healthy development in a synergistic way by affecting growth, maturation of the immune system, from innate to adaptive immunity, and the gut. A comprehensive overview of the human milk proteome, covering all of its components, is lacking, even though numerous analyses of human milk proteins have been reported. Such data could substantially aid in our understanding of the functionality of each constituent of the proteome. This review will highlight each of the aforementioned components of human milk and emphasize the functionality of the proteome throughout lactation, including nutrient delivery and enhanced bioavailability of nutrients for growth, cognitive development, immune defense, and gut maturation."

Open access: https://www.mdpi.com/2072-6643/11/8/1834/htm

Celebrating World Breastfeeding Week August 1st - 8th with Some New Studies on Human & Other Mammalian Milks

Title: Antitumor effects of seleno-β-lactoglobulin on human breast cancer MCF-7 and MDA-MB-231 cells in vitro.

In: Toxicology In Vitro 2019 Jul 23:104607. doi: 10.1016/j.tiv.2019.104607. [Epub ahead of print]

Authors: Xu X, Feng Y, Chen X, Wang Q, Meng T, Liu A.

Abstract: "Seleno-β-lactoglobulin (Se-β-Lg) was synthesized using seleninic acid, an organoselenium compound, and β-lactoglobulin (β-Lg), an important component of milk. Previously, we have studied the effects of Se-β-Lg on hepatocellular carcinoma and gastric cancer cells. In this study, we investigated the antitumor effects of Se-β-Lg and its potential mechanisms of action against human breast cancer cells (MCF-7 and MDA-MB-231). The results showed that the half-maximal inhibitory concentrations (IC50) of Se-β-Lg were 40.84 μg/mL for MCF-7 cells and 46.04 μg/mL for MDA-MB-231 cells at 24 h, while the compound showed no cytotoxicity to normal breast cells. The involvement of reactive oxygen species (ROS) in the activation of the apoptotic signaling pathway by Se-β-Lg was demonstrated by the incubation of cells with 80 μg/mL Se-β-Lg and determination of the rates of apoptosis and intracellular ROS levels after the addition of 10 mM N-acetyl-l-cysteine, a ROS inhibitor. Our findings revealed highly potent anticancer activities of Se-β-Lg against breast cancer cells and suggested that the compound may be used as a chemopreventive agent for breast cancer. Furthermore, we thoroughly elucidated the antitumor mechanism of Se-β-Lg."

Abstract only: https://www.sciencedirect.com/science/article/pii/S0887233319301055?via%3Dihub

Title: Structural basis for broad substrate specificity of UDP-glucose 4-epimerase in the human milk oligosaccharide catabolic pathway of Bifidobacterium longum.

In: Scientific Reports 2019 Jul 31;9(1):11081. doi: 10.1038/s41598-019-47591-w.

Authors: Nam YW, Nishimoto M, Arakawa T, Kitaoka M, Fushinobu S.

Abstract: "Infant gut-associated bifidobacteria has a metabolic pathway that specifically utilizes lacto-N-biose I (Gal-β1,3-GlcNAc) and galacto-N-biose (Gal-β1,3-GalNAc) from human milk and mucin glycans. UDP-glucose 4-epimerase (GalE) from Bifidobacterium longum (bGalE) catalyzes epimerization reactions of UDP-Gal into UDP-Glc and UDP-GalNAc into UDP-GlcNAc with the same level of activity that is required to send galacto-hexoses into glycolysis. Here, we determined the crystal structures of bGalE in three ternary complex forms: NAD+/UDP, NAD+/UDP-GlcNAc, and NAD+/UDP-Glc. The broad specificity of bGalE was explained by structural features of the binding pocket for the N-acetyl or C2 hydroxy group of the substrate. Asn200 is located in a pocket of the C2 group, and its side chain adopts different conformations in the complex structures with UDP-Glc and UDP-GlcNAc. On the other side, Cys299 forms a large pocket for the C5 sugar ring atom. The flexible C2 pocket and the large C5 pocket of bGalE are suitable for accommodating both the hydroxy and N-acetyl groups of the substrate during sugar ring rotation in the catalytic cycle. The substrate specificity and active site structure of bGalE were distinct from those of Esherichia coli GalE but similar to those of human GalE."

Open access: https://www.nature.com/articles/s41598-019-47591-w

Title: Macronutrient analysis of preterm human milk using mid-infrared spectrophotometry.

In: Journal of Perinatal Medicine 2019 Jul 31. pii: /j/jpme.ahead-of-print/jpm-2019-0105/jpm-2019-0105.xml. doi: 10.1515/jpm-2019-0105. [Epub ahead of print]

Authors: Bulut Ö, Çoban A, İnce Z.

Abstract: Background: "Human milk is the optimal source of nutrition for preterm infants. However, breast milk alone is often not sufficient to satisfy the high nutritional needs for growth and development in preterm infants. Fortified human breast milk is the best way to meet the nutritional needs of preterm infants. Human breast milk is fortified according to the estimated nutrient content of mature breast milk; however, because the content of breast milk is highly variable, the macronutrient support may be more or less than needed. The goal of this study was to analyze the macronutrient content of preterm human milk during the first 6 weeks of lactation." Methods: "The study included 32 mothers of preterm infants with a gestational age of ≤32 weeks. Breast milk was collected in 24-h cycles and analyzed daily using mid-infrared (MIR) spectroscopy. We measured protein, fat and lactose concentrations in the breast milk, and the energy content was calculated." Results: "The protein content was high during the first weeks of lactation, but decreased as lactation progressed. The fat, energy and lactose contents of the breast milk were low during the first 2 weeks of lactation, increased as lactation progressed and remained constant thereafter. In women with high body mass index (BMI), higher protein levels were found in transitional milk. In women who had high income level, higher fat and energy levels were found in transitional milk." Conclusion: "Our findings indicate that the macronutrient content of preterm breast milk changes throughout the course of lactation, with BMI and income level. Knowledge of the macronutrient composition of breast milk is necessary to ensure that preterm infants receive the appropriate types and quantities of nutrients to promote optimal growth, and to ensure that breast milk is fortified according to individual needs. Our findings may be useful for the provision of optimal nutritional support for preterm infants."

Abstract only: https://www.degruyter.com/view/j/jpme.ahead-of-print/jpm-2019-0105/jpm-2019-0105.xml

Title: Validation and Application of Biocrates AbsoluteIDQ® p180 Targeted Metabolomics Kit Using Human Milk.

In: Nutrients 2019 Jul 26;11(8). pii: E1733. doi: 10.3390/nu11081733.

Authors: Hampel D, Shahab-Ferdows S, Hossain M, Islam MM, Ahmed T, Allen LH.

Abstract: "Human-milk-targeted metabolomics analysis offers novel insights into milk composition and relationships with maternal and infant phenotypes and nutritional status. The Biocrates AbsoluteIDQ® p180 kit, targeting 40 acylcarnitines, 42 amino acids/biogenic amines, 91 phospholipids, 15 sphingolipids, and sum of hexoses, was evaluated for human milk using the AB Sciex 5500 QTRAP mass-spectrometer in liquid chromatography-tandem mass-spectrometry (LC-MS/MS) and flow-injection analysis (FIA) mode. Milk (<6 months lactation) from (A) Bangladeshi apparently healthy mothers (body mass index (BMI) > 18.5; n = 12) and (B) Bangladeshi mothers of stunted infants (height-for-age Z (HAZ)-score <-2; n = 13) was analyzed. Overall, 123 of the possible 188 metabolites were detected in milk. New internal standards and adjusted calibrator levels were used for improved precision and concentration ranges for milk metabolites. Recoveries ranged between 43% and 120% (coefficient of variation (CV): 2.4%-24.1%, 6 replicates). Milk consumed by stunted infants vs. that from mothers with BMI > 18.5 was lower in 6 amino acids/biogenic amines but higher in isovalerylcarnitine, two phospholipids, and one sphingomyelin (p < 0.05 for all). Associations between milk metabolites differed between groups. The AbsoluteIDQ® p180 kit is a rapid analysis tool suitable for human milk analysis and reduces analytical bias by allowing the same technique for different specimens. More research is needed to examine milk metabolite relationships with maternal and infant phenotypes."

Open access: https://www.mdpi.com/2072-6643/11/8/1733

Title: Polyamines in Food.

In: Frontiers in Nutrition 2019 Jul 11;6:108. doi: 10.3389/fnut.2019.00108. eCollection 2019.

Authors: Muñoz-Esparza NC, Latorre-Moratalla ML, Comas-Basté O, Toro-Funes N, Veciana-Nogués MT, Vidal-Carou MC.

Abstract: "The polyamines spermine, spermidine, and putrescine are involved in various biological processes, notably in cell proliferation and differentiation, and also have antioxidant properties. Dietary polyamines have important implications in human health, mainly in the intestinal maturation and in the differentiation and development of immune system. The antioxidant and anti-inflammatory effect of polyamine can also play an important role in the prevention of chronic diseases such as cardiovascular diseases. In addition to endogenous synthesis, food is an important source of polyamines. Although there are no recommendations for polyamine daily intake, it is known that in stages of rapid cell growth (i.e., in the neonatal period), polyamine requirements are high. Additionally, de novo synthesis of polyamines tends to decrease with age, which is why their dietary sources acquire a greater importance in an aging population. Polyamine daily intake differs among to the available estimations, probably due to different dietary patterns and methodologies of data collection. Polyamines can be found in all types of foods in a wide range of concentrations. Spermidine and spermine are naturally present in food whereas putrescine could also have a microbial origin. The main polyamine in plant-based products is spermidine, whereas spermine content is generally higher in animal-derived foods. This article reviews the main implications of polyamines for human health, as well as their content in food and breast milk and infant formula. In addition, the estimated levels of polyamines intake in different populations are provided."

Open access: https://www.frontiersin.org/articles/10.3389/fnut.2019.00108/full

Title: Tetrabromobisphenol A: Disposition, kinetics and toxicity in animals and humans. [Review article]

In: Environmental Pollution 2019 Jul 13;253:909-917. doi: 10.1016/j.envpol.2019.07.067. [Epub ahead of print]

Authors: Yu Y, Yu Z, Chen H, Han Y, Xiang M, Chen X, Ma R, Wang Z.

Abstract: "Tetrabromobisphenol A (TBBPA) is a nonregulated brominated flame retardant with a high production volume, and it is applied in a wide variety of consumer products. TBBPA is ubiquitous in abiotic matrices, wildlife and humans around the world. This paper critically reviews the published scientific data concerning the disposition, metabolism or kinetics and toxicity of TBBPA in animals and humans. TBBPA is rapidly absorbed and widely distributed among tissues, and is excreted primarily in the feces. In rats, TBBPA and its metabolites have limited systemic bioavailability. TBBPA has been detected in human milk in the general population. It is available to both the developing fetus and the nursing pups following maternal exposure. It has been suggested that TBBPA causes acute toxicity, endocrine disruptor activity, immunotoxicity, neurotoxicity, nephrotoxicity, and hepatotoxicity in animals. Cell-based assays have shown that TBBPA can induce reactive oxygen species in a concentration-dependent manner, and it promotes the production of inflammatory factors such as TNF α, IL-6, and IL-8. Cells exposed to high levels of TBBPA exhibit seriously injured mitochondria and a dilated smooth endoplasmic reticulum. This review will enhance the understanding of the potential risks of TBBPA exposure to ecological and human health."

Abstract only: https://www.sciencedirect.com/science/article/pii/S0269749119310188?via%3Dihub

Anti-Cancer Activity Found in Three Lactobacillus Strains in Human Milk

New research from the People's Republic of China:

Title: Anti-tumor potential of cell free culture supernatant of Lactobacillus rhamnosus strains isolated from human breast milk.

In: Food Research International 2019 Sep;123:286-297. doi: 10.1016/j.foodres.2019.05.002. Epub 2019 May 3.

Authors: Riaz Rajoka MS, Zhao H, Mehwish HM, Li N, Lu Y, Lian Z, Shao D, Jin M, Li Q, Zhao L, Shi J.

Abstract: "Lactobacilli rhamnosus has been characterized as a probiotic and plays an important role in human health by stimulating the supplement of nutrients, preventing the colonization of pathogens, and influencing the immune system. This study investigated the anticancer activity of the three Lactobacillus rhamnosus strains SHA111, SHA112, and SHA113 isolated from human breast milk. The cell-free supernatant of a liquid culture of the three strains showed excellent antioxidant activities against DPPH free radicals, superoxide anion radicals, and hydroxyl radicals; furthermore, significant anticancer activity was found on cervix cancer cells (HeLa) via cytotoxicity and induction of apoptosis. RT-qPCR and western blot analysis showed the induction of apoptosis was achieved via the up-regulation of BAD, BAX, Caspase3, Caspase8, Caspase9, and down-regulation of BCL-2 genes in HeLa cells. The results suggest that these strains have potential anticancer capability."

KEYWORDS: Antioxidant; Antitumor; Apoptosis; Lactobacillus; Probiotics

https://www.ncbi.nlm.nih.gov/pubmed/31284979

New Research on Essential Metabolites in Breastfed vs. Formula-Fed Micro-Preemies

This ScienceDaily news release discusses new research in micro-preemies using proton magnetic resonance spectroscopy, a non-invasive imaging technique that describes the chemical composition of specific brain structures and enables measurement of metabolites essential for growth. The multi-disciplinary team is comprised of lead author and neonatologist Katherine M. Ottolini, M.D.; Nickie Andescavage, M.D., Attending, Neonatal-Perinatal Medicine and co-author; Kushal Kapse, research and development staff engineer and co-author; Sudeepta Basu, M.D., neonatologist and co-author; and Catherine Limperopoulos, Ph.D., director of MRI Research of the Developing Brain and senior author, all of Children's National in Washington, D.C.

From the news release:

"Each chemical has its own a unique spectral fingerprint . . . . The team generated light signatures for key metabolites and calculated the quantity of each metabolite. Of note:

"Cerebral white matter spectra showed significantly greater levels of inositol (a molecule similar to glucose) for babies fed breast milk, compared with babies fed formula.

"Cerebellar spectra had significantly greater creatine levels for breastfed babies compared with infants fed formula. And the percentage of days infants were fed breast milk was associated with significantly greater levels of both creatine and choline, a water soluble nutrient."

New Study on Microbial Growth on Fortified and Unfortified Donor Human Milk in a NICU Setting

New study from the U.S.:

Title: Bacterial Content of Fortified and Unfortified Holder Pasteurized Donor Human Milk during Prolonged Refrigerated Storage

In: Journal of Pediatric Gastroenterology and Nutrition 2019 June 20. Authors: Mandru C, Perrin MT, Iyer R, Liveris D, Schwartz I, Alpan G1, Parvez B.

Results: "96.5% of milk samples manipulated in a vertical laminar flow hood were negative for bacterial growth. In the remainder 3.5% of the samples the maximum growth was 1 colony forming unit/ 0.1 ml plated. Higher colony counts were observed when the laminar hood was not used. In all cases, the colonies represented common skin bacteria and demonstrated an inconsistent and unsustained growth. Fortifier status and storage time were not significantly associated with increased bacterial growth (P > 0.05).”

Conclusions: "Unfortified and fortified Holder pasteurized donor human milk remain largely free of bacterial growth for up to 96 hours of refrigerated storage in NICU settings. Sample handling techniques are important for preventing microbial contamination." Abstract only: https://www.ncbi.nlm.nih.gov/pubmed/31232828

Dr. Ruth Lawrence's Oral History

Lori Feldman-Winter MD interviewed Dr. Ruth Lawrence in 2014 as part of the Oral History Project through the American Academy of Pediatrics’ Pediatric History Center:

https://www.aap.org/en-us/Documents/Lawrence_ruth_oral_history.pdf

Sleep Strengthens Memory in Infancy

From birth and across the lifespan, sleep in critical for gradually building memories into a robust state termed consolidation.

The repetition of practice as well as sleep both play integral roles in gradually building sensory-perceptual-motor memory for the acquisition of infant breastfeeding skills. Clinicians commonly observe increases in the infant’s speed and accuracy for achieving and sustaining the oral grasp of the nipple-areolar complex in subsequent feedings, as well as improvements in organized, effective suckling when a nursing session is followed by a long or short nap, in the absence of any interference in the infant’s learning to feed, and in the absence of significant learning constraints, i.e., task constraints (such as inverted nipple anatomy) and/or individual constraints (such as complete cleft of the lip and palate).

Interference is a theory that forgetting is caused by other learned information. Interference is heavily studied in the cognitive sciences, including the role of sleep in supporting the consolidation and reconsolidation of labile memories.

Newly formed memories are fragile, including motor memories. For example, the earliest memory for a newly created computer password is fragile until we perform enough repetition of that specific new password. In addition, we must have rest and sleep between practice sessions in order to further process these fragile new memories into an increasingly robust state of memory, termed consolidation.

In their 1995 seminal paper providing the first formal definition for the phenomenon of “nipple confusion,” Neifert et al. cited interference as a factor in the observable breastfeeding difficulties displayed by many infants following a learning experience with an artificial nipple, reflecting the fragility of early motor memories for the oral grasp and/or effective suckling for adequate transfer of milk.

Neifert M, Lawrence R, Seacat J.  Nipple confusion: Toward a formal definition.  The Journal of Pediatrics June 1995;126(6):S125-S129

Some new studies from 2018 and 2019 on sleep’s role in building memory:

Title: Sleep-dependent selective imitation in infants.

In: Journal of Sleep Research 2019 Feb;28(1):e12777. doi: 10.1111/jsr.12777.

Authors: Konrad C, Dirks ND, Warmuth A, Herbert JS, Schneider S, Seehagen S.

Open access: https://onlinelibrary.wiley.com/doi/epdf/10.1111/jsr.12777

From the summary: “Sleep might help infants selectively ‘discard’ aspects of a learning experience that they identify as being not useful or relevant in the future.”

Title: Sleep accelerates re-stabilization of human declarative memories.

In: Neurobiology of Learning and Memory 2019 Apr 25;162:1-8. doi: 10.1016/j.nlm.2019.04.012.

Authors: Moyano MD, Diekelmann S, Pedreira ME, Forcato C.

Abstract only: https://www.sciencedirect.com/science/article/pii/S1074742719300796?via%3Dihub

From the summary: “Consolidated memories can return to a labile state upon presentation of a reminder, followed by a period of re-stabilization known as reconsolidation . . . . Sleep plays a fundamental role in the consolidation and integration of new memories, and recently sleep has also been implicated in memory reconsolidation . . . . These findings suggest that 90 min of sleep accelerate memory re-stabilization after reminder presentation, shortening the reconsolidation time window and protecting the memory against subsequent interference. This rapid memory re-stabilization may depend on slow oscillation activity during NREM sleep.”

Title: Memory in 3-month-old infants benefits from a short nap.

In: Developmental Science 2018 May;21(3):e12587. DOI: 10.1111/desc.12587.

Authors: Horváth K, Hannon B, Ujma PP, Gombos F, Plunkett K.

Abstract only: https://www.ncbi.nlm.nih.gov/pubmed/28722249

The abstract: “A broad range of studies demonstrate that sleep has a facilitating role in memory consolidation (see Rasch & Born, 2013). Whether sleep-dependent memory consolidation is also apparent in infants in their first few months of life has not been investigated. We demonstrate that 3-month-old infants only remember a cartoon face approximately 1.5-2 hours after its first presentation when a period of sleep followed learning. Furthermore, habituation time, that is, the time to become bored with a stimulus shown repetitively, correlated negatively with the density of infant sleep spindles, implying that processing speed is linked to specific electroencephalographic components of sleep. Our findings show that without a short period of sleep infants have problems remembering a newly seen face, that sleep enhances memory consolidation from a very early age, highlighting the importance of napping in infancy, and that infant sleep spindles may be associated with some aspects of cognitive ability.”

New Study on the Enduring Effects of Positive Mother-Child Interactions

From the ScienceDaily news release: “Interactions between a mother and her child have been linked to cognitive outcomes in childhood, but little work has looked at farther-reaching effects. In a new study that examined data from the Wisconsin Longitudinal Study, more positive mother-child interactions during the first 16 years of life predicted higher education in adulthood, which predicted less decline in episodic memory, or the memory of autobiographical events.”

https://www.sciencedaily.com/releases/2019/05/190509080042.htm

Title: The enduring effects of mother-child interactions on episodic memory in adulthood.

In: Journal of Marriage and Family 2019; DOI: 10.1111/jomf.12569

Authors: Sharifian N, Zahodne LB.

Open access: https://onlinelibrary.wiley.com/doi/epdf/10.1111/jomf.12569

New Study from Denmark and Diabetologia

Title: Breastfeeding at night is rarely followed by hypoglycaemia in women with type 1 diabetes using carbohydrate counting and flexible insulin therapy.

In: Diabetologia 2019 Mar;62(3):387-398. doi: 10.1007/s00125-018-4794-9. Epub 2019 Jan 3.

Authors: Ringholm L, Roskjær AB, Engberg S, Andersen HU, Secher AL, Damm P, Mathiesen ER.

From the abstract: "Aims/hypothesis: Hypoglycaemia in association with breastfeeding is a feared condition in mothers with type 1 diabetes. Thus, routine carbohydrate intake at each breastfeed, particularly at night, is often recommended despite lack of evidence. We aimed to evaluate glucose levels during breastfeeding, focusing on whether night-time breastfeeding induced hypoglycaemia in mothers with type 1 diabetes.

"The percentage of night-time spent in hypoglycaemia was low in the breastfeeding mothers with type 1 diabetes and was similar in the control women. Breastfeeding at night-time rarely induced hypoglycaemia. The historical recommendation of routine carbohydrate intake at night-time breastfeeding may be obsolete in mothers with type 1 diabetes who have properly reduced insulin dose with sufficient carbohydrate intake."

Open access: https://link.springer.com/content/pdf/10.1007%2Fs00125-018-4794-9.pdf

New Study on Normal Breast Changes and the Survival of Pre-Malignant Breast Cells

On reversible vs. irreversible involution and much more:

Title: Autophagy and unfolded protein response (UPR) regulate mammary gland involution by restraining apoptosis-driven irreversible changes.

In: Cell Death Discovery, 2018; 5 (1) DOI: 10.1038/s41420-018-0105-y

Authors: Wärri A, Cook KL, Hu R, Jin L, Zwart A, Soto-Pantoja DR, Liu J, Finkel T, Clarke R.

Open access: https://www.nature.com/articles/s41420-018-0105-y

ScienceDaily press release: www.sciencedaily.com/releases/2018/10/181015084617.htm

Seeding the Infant Gut: New Study on the Human Milk Microbiome Specific to Yeast and Fungi

The researchers in this new study had previously studied the human milk (HM) microbiome in mothers living in Spain. In their new study, HM samples were obtained from outside Spain, including Finland, China, and South Africa, and their findings support the existence of a "breast milk mycobiota" under healthy conditions.

The most prevalent organisms in HM samples across different countries were from the genera Malassezia and Davidiella. The human milk microbiome was also compared in mothers who had given birth vaginally with that from mothers who had birthed via cesarean section. Among mothers delivering vaginally, certain fungi were more prevalent, including those of the genus Cryptococcus, although “mode of delivery made no difference in fungal diversity or richness.”

Title: Mycobiome Profiles in Breast Milk from Healthy Women Depend on Mode of Delivery, Geographic Location, and Interaction with Bacteria.

In: Applied and Environmental Microbiology 2019 Apr 18;85(9). pii: e02994-18. doi: 10.1128/AEM.02994-18.

Authors: Alba Boix-Amorós, Fernando Puente-Sánchez, Elloise du Toit, Kaisa M. Linderborg, Yumei Zhang, Baoru Yang, Seppo Salminen, Erika Isolauri, Javier Tamames, Alex Mira, Maria Carmen Collado. 

Abstract: https://www.ncbi.nlm.nih.gov/pubmed/?term=Mycobiome+Profiles+in+Breast+Milk+from+Healthy+Women+Depend+on+Mode+of+Delivery%2C+Geographic+Location%2C+and+Interaction+with+Bacteria.

The ScienceDaily press release: www.sciencedaily.com/releases/2019/03/190301133843.htm

New Study on Kynurenic Acid in Mammalian Milks

This interesting new study from Poland on kynurenic acid (KYNA) in mammalian milks found a possible role for KYNA as an anti-obesogen by influencing metabolism and weight gain. Researchers found higher levels of KYNA in human milk versus markedly lower levels in artificial infant milks. "In the context of lifelong obesity observed worldwide in children fed artificially, our results imply that insufficient amount of KYNA in baby formulas could be considered as one of the factors associated with increased mass gain."

Title: Kynurenic acid as the neglected ingredient of commercial baby formulas.

In: Scientific Reports 2019 Apr 15;9(1):6108. doi: 10.1038/s41598-019-42646-4.

Authors: Milart P, Paluszkiewicz P, Dobrowolski P, Tomaszewska E, Smolinska K, Debinska I, Gawel K, Walczak K, Bednarski J, Turska M, Raban M, Kocki T, Turski WA.

Abstract: "The global increase in resorting to artificial nutritional formulas replacing breastfeeding has been identified among the complex causes of the obesity epidemic in infants and children. One of the factors recently recognized to influence metabolism and weight gain is kynurenic acid (KYNA), an agonist of G protein-coupled receptor (GPR35). Therefore the aim of the study was to determine the concentration of KYNA in artificial nutritional formulas in comparison with its level in human breast milk and to evaluate developmental changes in rats exposed to KYNA enriched diet during the time of breastfeeding. KYNA levels were measured in milk samples from 25 healthy breast-feeding women during the first six months after labor and were compared with 21 time-adjusted nutritional formulas. Animal experiments were performed on male Wistar rats. KYNA was administered in drinking water. The content of KYNA in human milk increases more than 13 times during the time of breastfeeding while its level is significantly lower in artificial formulas. KYNA was detected in breast milk of rats and it was found that the supplementation of rat maternal diet with KYNA in drinking water results in its increase in maternal milk. By means of the immunoblotting technique, GPR35 was evidenced in the mucosa of the jejunum of 1-day-old rats and distinct morphological changes in the jejunum of 21-day-old rats fed by mothers exposed to water supplemented with KYNA were found. A significant reduction of body weight gain of rats postnatally exposed to KYNA supplementation without changes in total body surface and bone mineral density was observed. The rat offspring fed with breast milk with artificially enhanced KYNA content demonstrated a lower mass gain during the first 21 days of life, which indicates that KYNA may act as an anti-obesogen. Further studies are, therefore, warranted to investigate the mechanisms regulating KYNA secretion via breast milk, as well as the influence of breast milk KYNA on mass gain. In the context of lifelong obesity observed worldwide in children fed artificially, our results imply that insufficient amount of KYNA in baby formulas could be considered as one of the factors associated with increased mass gain."

Open access: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465401/

New Study on the Milk Biome in Expressed Milk vs. Milk Via Direct Breastfeeding

From the press release:

“'We found that milk bacteria are different in mothers who pump their milk,'” said Dr. Meghan Azad, the University of Manitoba investigator who led the study. “'We suspect that pumping may prevent the transfer of oral bacteria from the infant to the mother and might introduce other bacteria from the pump. Therefore, contrary or in addition to the hypothesis that milk bacteria come from the mother’s gut, our results suggest that the infant’s oral bacteria are important in shaping the milk microbiota.'"

Title: Composition and Variation of the Human Milk Microbiota Are Influenced by Maternal and Early-Life Factors.

Authors: Moossavi S, Sepehri S, Robertson B, Bode L, Goruk S, Field CJ, Lix LM, de Souza RJ, Becker AB, Mandhane PJ, Turvey SE, Subbarao P, Moraes TJ, Lefebvre DL, Sears MR, Khafipour E, Azad MB.

In: Cell Host & Microbe 2019 Feb 13;25(2):324-335.e4. doi: 10.1016/j.chom.2019.01.011.

Press release: https://childstudy.ca/media/press-releases/breastmilk-microbiome/

Summary with references: https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(19)30049-6

Summary: "Breastmilk contains a complex community of bacteria that may help seed the infant gut microbiota. The composition and determinants of milk microbiota are poorly understood. Among 393 mother-infant dyads from the CHILD cohort, we found that milk microbiota at 3-4 months postpartum was dominated by inversely correlated Proteobacteria and Firmicutes, and exhibited discrete compositional patterns. Milk microbiota composition and diversity were associated with maternal factors (BMI, parity, and mode of delivery), breastfeeding practices, and other milk components in a sex-specific manner. Causal modeling identified mode of breastfeeding as a key determinant of milk microbiota composition. Specifically, providing pumped breastmilk was consistently associated with multiple microbiota parameters including enrichment of potential pathogens and depletion of bifidobacteria. Further, these data support the retrograde inoculation hypothesis, whereby the infant oral cavity impacts the milk microbiota. Collectively, these results identify features and determinants of human milk microbiota composition, with potential implications for infant health and development.”

Some New Studies

Title: Identification of Differentiating Metabolic Pathways between Infant Gut Microbiome Populations Reveals Depletion of Function-Level Adaptation to Human Milk in the Finnish Population.

In: mSphere 2019 Mar 20;4(2). pii: e00152-19. doi: 10.1128/mSphereDirect.00152-19.

Authors: Majta J, Odrzywolek K, Milanovic B, Hubar V, Wrobel S, Strycharz-Angrecka E, Wojciechowski S, Milanowska K.

Open access: https://msphere.asm.org/content/msph/4/2/e00152-19.full.pdf

Title: Relationship of Necrotizing Enterocolitis Rates to Adoption of Prevention Practices in US Neonatal Intensive Care Units.

In: Advances in Neonatal Care 2019 Mar 19. doi: 10.1097/ANC.0000000000000592. [Epub ahead of print]

Authors: Gephart SM, Quinn MC.

Abstract: https://www.ncbi.nlm.nih.gov/pubmed/30893097

Title: A Pilot Study of Oxytocin in Low-Income Women With a Low Birth-Weight Infant: Is Oxytocin Related to Posttraumatic Stress?

In: Advances in Neonatal Care 2019 Mar 19. doi: 10.1097/ANC.0000000000000601. [Epub ahead of print]

Authors: Garfield L, Holditch-Davis D, Carter CS, McFarlin BL, Seng JS, Giurgescu C, White-Traut R.

Abstract: https://www.ncbi.nlm.nih.gov/pubmed/30893095

Title: Determination of four parabens and bisphenols A, F and S in human breast milk using QuEChERS and liquid chromatography coupled to mass spectrometry.

In: Journal of Chromatography B, Analytical Technologies in the Biomedical and Life Sciences 2019 Mar 7. pii: S1570-0232(18)31845-2. doi: 10.1016/j.jchromb.2019.03.004. [Epub ahead of print]

Authors: Dualde P, Pardo O, F Fernández S, Pastor A, Yusà V.

Abstract: https://www.sciencedirect.com/science/article/pii/S1570023218318452?via%3Dihub

Quote of the Day

The following quote from neurophysiologist Mark Hallett reinforces the recommendation in Step 9 from the World Health Organization (WHO) and UNICEF’s Ten Steps to Successful Breastfeeding, which infers that learning infant breastfeeding skills is dependent upon practice that is specific to the task (The Specificity Principle). The Ten Steps are one aspect of the Baby Friendly Hospital Initiative, and from 1986 to early 2018, Step 9 advised to “Give no artificial nipples to breastfeeding infants.” The language of the Ten Steps was revised in 2018, and the current language of Step 9 now states, “Counsel mothers on the use and risks of feeding bottles, teats and pacifiers.”

Quote of the Day from Mark Hallett, M.D.:

Immediately after learning, the motor memory is fragile. In particular, it is vulnerable to disruption by learning of something similar.  However, if there is no disruption, with the passage of time, the memory becomes more robust. It is this process, of becoming more and more robust with time, that is designated consolidation.

In: Hallett M (2006).  The role of the motor cortex in motor learning.  In Motor Control and Learning (Latash ML & Lestienne F, Eds.), p. 92.  New York: Springer.

Dr. Hallett developed and has maintained the Human Motor Control Section (HMCS) at the National Institutes of Health in Bethesda, Maryland.

Hallett’s faculty profile:

https://neuroscience.nih.gov/ninds/Faculty/Profile/mark-hallett.aspx   

Article: “Celebrating Mark Hallett’s 30 Years of Research”:

https://irp.nih.gov/catalyst/v22i4/human-motor-control

Dr. Hallett’s interview from NIH’s Oral History Program: https://history.nih.gov/archives/downloads/halletinterview.pdf

Quote of the Day

When a baby has not yet learned or re-learned the oral grasp of the nipple-areolar complex, a primary and critical recommendation from the clinician is skin-to-skin contact ad lib between members of the dyad. As an IBCLC, I especially appreciate these passages from Saffran & Kirkham on the visual environment, spatial learning, and the impact of anticipatory behavior:

“Learning itself is affected by complexity . . . . infants were as capable in the visual domain as in the auditory domain . . . . However, an important aspect of the ability to perceive the visual environment as coherent and intelligible is understanding objects’ spatial locations and what their present locations might predict about future events. Acquisition of this type of knowledge is essential for motion perception and for the production of action sequences; one has to learn not only which actions are appropriate, but also where and when they should be performed. For example, if, while looking out the window of your house, you see the child walking up the path to the front door, you can reasonably predict that you will see her next in the doorway of your house. You can use this information to guide appropriate anticipatory behavior, such as moving to a location that provides a view of the door to greet your child as she comes inside. In other words, each visual event is temporally related both to the previous event and to the future event and occurs within a spatial context.”

Authors: Jenny R. Saffran and Natasha Z. Kirkham

Journal (review) article title: Infant Statistical Learning.

In: Annual Reviews of Psychology 2018 January 04;69:181-203. DOI: 10.1146/annurev-psych-122216-011805

Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754249/pdf/nihms910586.pdf

In Celebration of the IBCLC

In honor of IBCLCs around the world, and in celebration of IBCLC Day on this date:

The work of the IBCLC is always interesting. Sometimes our work is straightforward and uncomplicated, and we often provide our clinical skills in support of complex feeding situations. These feeding challenges range from mild in complexity to highly complex.

Kudos to IBCLCs everywhere, and to all others who support dyads and their families in infant feeding toward optimal health!

New Study: Sex-Specific Cardiac Benefits from Human Milk

This interesting new open access study found sex-specific benefits from human milk in regard to cardiac health.

Title: Content of n-3 LC-PUFA in Breast Milk Four Months Postpartum is Associated with Infancy Blood Pressure in Boys and Infancy Blood Lipid Profile in Girls.

In: Nutrients 2019, 11(2), 235; https://doi.org/10.3390/nu11020235

Authors: Signe Bruun, Lenie van Rossem, Lotte Lauritzen, Steffen Husby, Lotte Neergaard Jacobsen, Kim F. Michaelsen, Maria Boysen Sandberg, Ken D. Stark, Jan Sørensen and Gitte Zachariassen.

From the abstract: "Based on 336 mother-child dyads, high n-3 LC-PUFA in breast milk was inversely associated with systolic and diastolic BP in boys at 4 months (β = −20.0 (95% CI = −33.4, −6.7), p = 0.004 and β = −10.2 (95% CI = −19.8, −0.5), p = 0.039, respectively); inversely associated with HDL cholesterol, and directly associated with triglyceride in girls at 4 months (β = −0.7 (95% CI = −1.1, −0.3), p = 0.001 and β = 3.1 (95% CI = 1.0, 5.2), p = 0.005, respectively) . . . . Our results indicate that early intake of n-3 LC-PUFA can affect early development in cardiometabolic factors such as BP and BLP in a sex-specific manner."

On Skin-to-Skin Contact, Associative Learning, and Reward-Based Learning

Across the lifespan, the learning of all feeding and drinking skills reflects procedural learning, reinforcement learning, reward-based learning, and associative learning. During associative learning, we learn to predict relationships, such as between two or more stimuli, a stimulus and a response, and between a response and its consequence.

For young newborns, learning milk-feeding skills is supported and hastened by the primitive survival reflexes, pre-adapted movements that are further adapted during sensory-perceptual-motor learning. The crawl reflex enables us to “drive” to nature’s first restaurant, and the rooting reflex further orients us to the dining location. As the infant determines the action (action planning) of moving still closer toward the nipple-areolar complex, a reflexive lunge is displayed by the infant toward the breast, in tandem with a reflexive wide open gape, with the tongue extended over the lower alveolar ridge. When the baby learns how to achieve and sustain the oral grasp, the suck reflex is soon stimulated. In mutuality and reciprocity between both members of the dyad, milk is released via the initial Milk Ejection Reflex (MER) as well as subsequent MERs in the same meal, much like service at a fine dining establishment, as one course at a time is served. Should the flow of milk temporarily overwhelm the young novice, the cough reflex helps us to reorganize our swallowing movements. With the repetition of practice, the baby’s suck reflex becomes increasingly more coordinated with the swallow reflex, in support of increasing motor control for the infant’s effective transfer of milk.

However, the remarkable presence of the primitive survival reflexes does not guarantee the oral grasp and effective sucking for all infant milk-feeding methods all the time. Following a learning experience with an artificial nipple and the subsequent return to the breast, skill decay (decreased speed and accuracy) is often observed for the baby’s oral grasp/latch at the breast, and/or effective sucking for adequate milk transfer, reflecting the cognitive demands of task-switching. These cognitive demands are particularly pronounced during early learning when memories are in their most fragile state, and furthermore, the younger we are, the greater the cognitive demands of task-switching.

When clinicians are called upon to assist the infant in a transfer of learning from artificial nipple to the breast, finger-feeding is often a highly effective technique in helping the infant learn to associate the smell, touch, and taste of the mother or other caregiver’s skin with sucking and receiving milk. In the language of the cognitive sciences, this pairing of associates is critical for learning and re-learning. However, the very first clinical recommendation is often skin-to-skin contact ad lib, also to familiarize the infant with that rich sensory milieu, including the visual field of that feeding location.

Susan Ludington, RN CNM PhD FAAN is the Executive Director of the United States Institute for Kangaroo Care (USIKC). Ludington has been studying skin-to-skin contact via Kangaroo Care since 1988, and offers this extensive annotated bibliography and reference list on the USIKC website. http://www.kangaroocareusa.org/uploads/KCBIB2018.pdf

Associative learning is heavily studied in the cognitive sciences, as is reward-based learning, reinforcement learning, and procedural learning. Some recent studies:

Title: Pavlovian reward learning elicits attentional capture by reward-associated stimuli.

Authors: Mine C, Saiki J.

In: Attention, Perception & Psychophysics 2018 Jul;80(5):1083-1095. doi: 10.3758/s13414-018-1502-2.

https://link.springer.com/article/10.3758%2Fs13414-018-1502-2

Title: I like it by mere association: Conditioning preferences in infants.

Authors: Jenny L Richmond, Jenna Zhao, Gabrielle Weidenmann.

In: Journal of Experimental Child Psychology 2017 September;161:19-31. doi: 10.1016/j.jecp.2017.03.015.

https://www.sciencedirect.com/science/article/pii/S0022096517302023?via%3Dihub

A new meta-analysis on associative word learning and task-switching in infancy:

Title: Associative word learning in infancy: A meta-analysis of the switch task.

Authors: Tsui ASM, Byers-Heinlein K, Fennell CT.

In: Developmental Psychology 2019 Feb 7. doi: 10.1037/dev0000699.

https://www.ncbi.nlm.nih.gov/pubmed/30730174

And one more: These authors reviewed neuroimaging studies of cognitive flexibility, with emphasis on set shifting and task switching. 

Title: Demystifying cognitive flexibility: Implications for clinical and developmental neuroscience.

Authors: Dajani DR, Uddin LQ.

In: Trends in Neurosciences 2015 Sep;38(9):571-8. doi: 10.1016/j.tins.2015.07.003.

Full text/author manuscript: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414037/pdf/nihms709425.pdf